Despite the development of numerous chemical agents and sophisticated regimens of drug therapy, the ravages of cancer continue to extract an ever-increasing human toll of suffering and death. Although many advances have been made, especially in the area of combination drug therapy, the need for new and better methods of treating neoplasms and leukemias has not diminished. This is especially evident in the area of inoperable or metastatic solid tumors, such as various forms of lung cancer.
While the treatment of cancer was once considered impossible, great strides have been made during the past tens years in controlling the ravages of this often fatal disease. Several drugs which contribute to the increasing rate of survival are now routinely used clinically. The most commonly employed antitumor agents include methotrexate, doxorubicin and vinca alkaloids such as vincristine. However, research continues in an attempt to develop more effective compounds with greater safety. This invention provides valuable improvements in the treatment of tumors.
EPO Patent Application Publication No. 184,365 describes the use of certain difluoronucleosides for the treatment of neoplasms in mammals. The antiviral use of some of these same nucleosides and methods for their preparation are disclosed in U.S. Pat. No. 4,526,988 and British Patent Application GB No. 2172287. These compounds were found to have useful activity against a variety of tumor systems in mice.
The present invention provides immunoglobulin conjugates of some of these difluoronucleosides. Although the general concept of conjugating drugs to antibodies is generally known, e.g., EPO Patent Application No. 88695, the literature clearly acknowledges the manner and means for which conjugation is accomplished can be critical to obtaining conjugates having useful biological properties. For example, where a compound or drug has more than one reactive functional group, attachment through one functionality may provide a conjugate with significantly greater or lesser biological activity as compared with conjugation through a different functional group. Similarly, the manner in which such conjugation occurs is often critical to the biological utility. In some instances, better biological activity is obtained by covalently linking the compound and antibody directly whereas in other cases a linking group of some type between the two moieties is preferred. Thus, in most cases, there is no way of predicting whether a particular manner of conjugation will provide a useful conjugate.